The malfunctioning of protein kinases (PKs) is the hallmark of numerous diseases. A large share of the oncogenes and proto-oncogenes involved in human cancers code for PKs. The enhanced activities of PKs are also implicated in many non-malignant diseases, such as benign prostate hyperplasia, familial adenomatosis, polyposis, neuro-fibromatosis, psoriasis, vascular smooth cell proliferation associated with atherosclerosis, pulmonary fibrosis, arthritis glomerulonephritis and post-surgical stenosis and restenosis. PKs are also implicated in inflammatory conditions and in the multiplication of viruses and parasites. PKs may also play a major role in the pathogenesis and development of neurodegenerative disorders.
For a general reference to PKs malfunctioning or disregulation see, for instance, Current Opinion in Chemical Biology 1999, 3, 459-465.
Phosphatidylinositol 3-kinases (PI3Ks) are a family of lipid and serine/threonine kinases that catalyze the phosphorylation of the membrane lipid phosphatidylinositol (PI) on the 3′-OH of the inositol ring to produce phosphoinositol-3-phosphate (PIP), phosphoinositol-3,4-diphosphate (PIP2) and phosphoinositol-3,4,5-triphosphate (PIP3), which act as recruitment sites for various intracellular signalling proteins, which in turn form signalling complexes to relay extracellular signals to the cytoplasmic face of the plasma membrane.
These 3′-phosphoinositide subtypes function as second messengers in intra-cellular signal transduction pathways (see e.g. Trends Biochem. Sci 22 87,267-72 (1997) by Vanhaesebroeck et al.; Chem. Rev. 101 (8), 2365-80 (2001) by Leslie et al (2001); Annu. Rev. Cell. Dev. Boil. 17, 615-75 (2001) by Katso et al; and Cell. Mol. Life Sci. 59 (5), 761-79 (2002) by Toker et al).
Multiple PI3K isoforms categorized by their catalytic subunits, their regulation by corresponding regulatory subunits, expression patterns and signalling specific functions (p110α, β, δ, γ) perform this enzymatic reaction (Exp. Cell. Res. 25 (1), 239-54 (1999) by Vanhaesebroeck and Katso et al., 2001, above).
The closely related isoforms p110α and β are ubiquitously expressed, while δ and γ are more specifically expressed in the haematopoietic cell system, smooth muscle cells, myocytes and endothelial cells (see e.g. Trends Biochem. Sci. 22 (7), 267-72 (1997) by Vanhaesebroeck et al). Their expression might also be regulated in an inducible manner depending on the cellular, tissue type and stimuli as well as disease context. Inductibility of protein expression includes synthesis of protein as well as protein stabilization that is in part regulated by association with regulatory subunits.
Eight mammalian PI3Ks have been identified so far, including four class I PI3Ks. Class Ia includes PI3Kα, PI3Kβ and PI3Kδ. All of the class Ia enzymes are heterodimeric complexes comprising a catalytic subunit (p110α, p110β or p110δ) associated with an SH2 domain containing p85 adapter subunit. Class Ia PI3Ks are activated through tyrosine kinase signalling and are involved in cell proliferation and survival. PI3Kα and PI3Kβ have also been implicated in tumorigenesis in a variety of human cancers. Thus, pharmacological inhibitors of PI3Kα and PI3Kβ are useful for treating various types of cancer.
PI3Kγ, the only member of the Class Ib PI3Ks, consists of a catalytic subunit p110γ, which is associated with a p110 regulatory subunit. PI3Kγ is regulated by G protein coupled receptors (GPCRs) via association with βγ subunits of heterotrimeric G proteins. PI3Kγ is expressed primarily in hematopoietic cells and cardiomyocytes and is involved in inflammation and mast cell function. Thus, pharmacological inhibitors of PI3Kγ are useful for treating a variety of inflammatory diseases, allergies and cardiovascular diseases.
These observations show that deregulation of phosphoinositol-3-kinase and the upstream and downstream components of this signalling pathway is one of the most common deregulations associated with human cancers and proliferative diseases (see e.g. Parsons et al., Nature 436:792 (2005); Hennessey et al., Nature Rev. Drug Discovery 4: 988-1004 (2005).
The listing or discussion of an apparently prior-published document in this specification should not necessarily be taken as an acknowledgement that the document is part of the state of the art or is common general knowledge.
International patent application WO 2007/064797 discloses various compounds that may be useful in the treatment of cancer. However, there is no mention in that document of imidazothiadiazoles.
US patent applications US 2007/0049591 and US 2007/0093490 and international patent application WO 2004/058769 all disclose various compounds that may be useful as kinase inhibitors. Further, international patent application WO 2007/0136736 discloses various compounds that may be useful as Lck inhibitors. However, all these documents only mention compounds in which the core ring structure is a 6,5-ring system.
International patent application WO 2004/111060 discloses various imidazothiadiazoles that may be useful in the treatment of neurodegenerative diseases and cancer. However, this document primarily relates to 6-aryl substituted imidazo[2,1-b]-1,3,4-thiadiazoles, substituted in the 2-position with a sulfur (or oxidised derivative thereof) linker group. Further, international patent application WO 03/051890 also discloses various imidazothiadiazoles, which may be useful in the treatment of neurodegenerative diseases and cancer. However, this document primarily relates to 6-aryl substituted imidazo[2,1-b]-1,3,4-thiadiazoles, substituted in the 2-position with a sulfonamide group.
Journal article European Journal of Medicinal Chemistry (2003), 38(7-8), 781-786 by Terzioglu et al discloses various compounds that may be useful in the treatment of cancer. However, this document only discloses compounds that contain a carbohydrazide moiety.
Italian journal article Arzneimittel-Forschung (2000), 50(6), 550-553 by Andreani et al discloses various compounds including specific imidazothiadiazoles. However, there is no mention in this journal article that the compounds disclosed therein may be useful as protein kinase inhibitors.
International patent application WO 97/11075 discloses various compounds imidazothiadiazoles as herbicides. However, there is no disclosure that such compounds may be useful as pharmaceuticals, e.g. in the treatment of cancer.
European patent application EP 662 477 and journal article Journal of the Indian Chemical Society (1979), 56(7), 716-17 by Joshi et al, both disclose various heterobicyclic compounds, including specific imidazolothiadiazole compounds, which may be active as fungicides. However, there is no disclosure in either of these documents that the compounds disclosed therein may be useful as protein kinase inhibitors.
Italian journal article Farmaco, Edizione Scientifica (1985), 40(3), 190-9 by Abignente et al and European patent application EP 41215 both disclose various imidazolothiadiazoles, which may have been tested for medicinal properties for research purposes.
Various imidazolothiadiazoles have also been disclosed in Journal of the Indian Chemical Society (1982), 59(10), 1170-3 as potential fungicides and/or bactericides.
International patent application WO 2009/040552 discloses various imidazolothiadiazole compounds for use as kinase inhibitors. However, this document does not predominantly relate to imidazolothiadiazoles directly substituted at the 2- and 5-position with an aromatic group.